Infection with herpes simplex virus (HSV) in adults is often subclinical, but in the newborn HSV is a significant cause of mortality and morbidity. Although differences in the immune response between the developing brain and the adult have been implicated in the increased severity of disease in the neonate, the precise reasons for this difference are unknown. The HSV protein ?34.5 is often described as the neurovirulence factor during HSV central nervous system (CNS) infection due to the finding that the deletion of this gene results in a significantly attenuated virus that has decreased replication in neurons. Prior studies have shown that the HSV ?34.5 protein is central to countering the type-I interferon response initiated by the host cell through multiple domains that function to (i) counter host-translational arrest through PKR, (ii) inhibit the TANK-binding kinase pathway, and (iii) inhibit te autophagic response through a domain that binds its initiating protein, beclin-1. Inhibition of autophagy by many neurotropic viruses, including HSV, is a critical function for pathogenesis in neurons, which use autophagy as a method to control viral replication and avoid a potentially devastating cytolytic response. In a murine model of adult HSV encephalitis, a beclin-1 binding domain (BBD) deficient ?34.5 mutant HSV-1 is unable to inhibit autophagy and is severely neuroattenuated in adult mice. Autophagy is up-regulated in the neonatal brain after birth and it also plays a critical role in neurodevelopment. My preliminary data suggests that unlike in the adult, the beclin-1-binding function of ?34.5 is dispensable for the pathogenesis of HSV in a model of neonatal encephalitis. However, deletion of the entire ?34.5 gene from HSV-1 still results in neuroattenuation in the neonatal brain. Therefore, I hypothesize that ?34.5 confers the neurovirulence of HSV in the neonate through a mechanism that is distinct from the inhibition of autophagy. Although autophagy appears to play a cytoprotective role in an adult model of HSV encephalitis, the role of autophagy in the unique environment of the neonatal brain has not yet been investigated. Recent work by groups investigating neonatal hypoxic-ischemic injury has demonstrated that dysregulated autophagy may contribute to increased apoptotic cell death in the neonatal brain. My preliminary data suggests an association between markers of activated autophagy and apoptosis in infected regions of the neonatal brain. Thus, I hypothesize that unlike in the adult, autophagy does not protect the newborn brain from HSV infection and activated autophagy leads to increased apoptotic cell death. I will elucidate the critical determinants of neuropathogenesis in the neonate compared to the adult using several mutant viruses that have been deleted in the ?34.5 regions critical for host-cell interaction. Using wild type and autophagy knockout mice, I will investigate the activation of autophagy in the infected neonatal CNS and the contribution of autophagy to apoptotic cell death.